Regulation of the Prostate Cancer Tumor Microenvironment.

摘要

The role of innate immunity in prostate cancer tumorigenesis is unclear. We hypothesis that innate immune pathways contribute to programming the inflammatory component of the tumor microenvironment and that activation of these pathways may selectively skew this immune composition and alter tumor growth. Pattern recognition receptors such as Toll-like receptors (TLRs) are key signaling molecules that regulate innate and adaptive immune responses in the presence of pathogens and endogenous ligands. We have generated and characterized TRAMP Tg+/- x MyD88-/- mice. We showed that de novo prostate cancers in absence of MyD88 develop higher grade adenocarcinomas than wild-type controls at 30 weeks of age. Analysis of tumor infiltrating cells revealed increased infiltration of macrophage lineage cells, characterized as myeloid-derived suppressor cells (MDSCs), and decreased CD8 T lymphocytes and NK cells. We have also shown that a serine/threonine kinase receptor-interacting protein 2 (Rip2) may play an important role in the intrinsic development of myeloid-derived suppressor cells. Current work focuses on characterizing the role of Rip2 in MDSC development and examining if activation of Rip2-dependent pathways can influence infiltration of MDSCs and prostate cancer growth.